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Journal of Clinical Virology 36 (2006) 13–16 Disseminate and fatal cytomegalovirus disease with thymitis in a naive HIV-patient after early initiation of HAART: Immune restoration disease? Sonia Gutiérrez a,1 , Silvia Alconchel b , Ezequiel Ruiz-Mateos c,1 , Miguel Genebat a,1 , Alejandro Vallejo c,1 , Eduardo Lissen a,1 , Jorge Fernández-Alonso b , Manuel Leal a,∗,1 a b Department of Internal Medicine, Virgen del Rocio University Hospital, Seville, Spain Department of Anatomy Pathology, Virgen del Rocio University Hospital, Seville, Spain c Department of Biochemistry, Virgen del Rocio University Hospital, Seville, Spain Received 5 October 2005; received in revised form 10 December 2005; accepted 16 December 2005 Abstract We describe a naı̈ve HIV-infected patient who developed a Pneumocystis carinii pneumonia and disseminate and fatal cytomegalovirus disease within 3 months after initiation of HAART, suggesting due to coincidence in time, an immune restoration disease. We propose an alternative hypothesis. © 2005 Elsevier B.V. All rights reserved. Keywords: Immune restoration disease; Thymitis cytomegalovirus; AIDS 1. Introduction HIV-patients under HAART may experience severe systemic inflammatory reactions that have been defined as immune restoration disease (IRD). It has been communicated that IRD has two different patterns; an earlier pattern during the first 3 months of HAART as an immune response against viable opportunistic pathogens, and a later pattern as an immune response against non-viable opportunistic pathogens months to years after HAART (French et al., 2004). During the IRD, a baseline CD4 cell count below 100 cells/mm3 has been reported among patients, while after HAART an increase above 200 cells/mm3 is reached (Price et al., 2001). Outcomes range from minimal morbidity to fatal progression (French et al., 2004; Hirsch et al., 2004). In this way, atypical presentations of mycobacterial, cytomegalovirus (CMV), ∗ Corresponding author at: Viral Hepatitis and AIDS Unit, Department of Internal Medicine, Virgen del Rocio University Hospital, Seville, PC 41013, Spain. Tel.: +34 955012396; fax: +34 955012390. E-mail address: [email protected] (M. Leal). 1 Viral Hepatitis and AIDS Unit. 1386-6532/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2005.12.007 hepatitis B virus, hepatitis C virus and JC virus have been described after initiating HAART (French et al., 2004; Safdar et al., 2002). We here report the case of a naı̈ve HIV-infected patient who developed Pneumocystis carinii pneumonia as well as disseminated and fatal CMV infection coinciding with the initiation of HAART. 2. Case report In 1993, a 32-year-old woman was diagnosed of HIV infection in our unit. Then, her CD4 T cell count was 840 cells/mm3 , and HIV plasma viral load (pVL) was above 75,000 copies/mL. The moment that primoinfection occurred in the past was unknown because it was asymptomatic. Since she declined to receive antiretroviral therapy, a progressive CD4+ T cell count decrease was taking place during the following 9 years. In July 2002, she began HAART with zidovudine, lamivudine, and abacavir, having HIV pVL above 75,000 copies/mL, CD4+ T cell count of 90 cells/mm3 , and a thymic volume (measured by mediastinic computed 14 S. Gutiérrez et al. / Journal of Clinical Virology 36 (2006) 13–16 tomography) of 1.2 cm3 . In the next 3 months after the initiation of HAART, the patient developed several infectious events such as P. carinii pneumonia after 10 days, which was successfully treated with cotrimoxazole. Seven days later, the patient showed low level of conscience, convulsions, and plasmatic Na+ concentration of 102 mequiv./L, recovering from the neurological events after hiponatremia treatment. Three weeks after the initiation of HAART, a colonoscopy was performed due to the development of mucosanguineous diarrhoea. The biopsy of the colon revealed cytomegalic inclusion bodies that allowed the diagnosis of CMV colitis, which was treated with ganciclovir and foscarnet, while HAART was interrupted after 6 weeks of its initiation due to an apparent IRD. She had not previously suffered a CMVrelated disease, thus, she did not take ganciclovir or foscarnet. Despite of this new treatment, symptoms as fever, cough, and disnea turned up, as well as bilateral interstitial infiltrate, which was evidenced by chest radiography. Since the patient treated with ganciclovir and foscarnet showed favourable evolution, empiric CMV pneumonia was diagnosed. Ten days later, the patient referred lost of vision and fundus ophthalmoscopic examination confirming CMV retinitis, despite the treatment she had taken. At that moment, CMV plasma viral load was above 738,000 copies/mL, it was not possible to achieve the sequence of CMV strain to study the development of drug related resistance to ganciclovir and foscarnet, so, due to the progression of CMV disease with this drugs we decided to switch to cidofovir. Since the patient progressed with adverse clinical events, IRD was ruled out and a new HAART regimen including zidovudine, lamivudine, and lopinavir/ritonavir was prescribed. Finally, although CD4 T cell count increased to 432 cells/mm3 and CMV viral load decreased to 1000 copies/mL, the patient developed fatal meningoencephalitis after 12 weeks of initiation of HAART. Necropsy was performed to further studies. 3. Material and methods Plasma HIV-1 RNA was measured by a quantitative PCR (HIV Monitor Test kit version 1.5, Roche Molecular System Inc., Branchburg, NJ) according to the manufacturer’s instructions. This assay has a detection limit of 50 HIV-1 copies/mL. Frozen plasma samples stored since 1993 were used to measure CMV viral load by a quantitative PCR (Cobas Amplicor CMV Monitor test, Roche Molecular Systems Inc., Branchburg, NJ) according to the manufacturer’s instructions. This assay has a detection limit of 400 CMVDNA copies/mL. Total CD4 cell count was determined in fresh samples by conventional flow cytometry. Since the patient was enrolled in a study about the role of the thymus in T cell repopulation, the following measured parameters were available: mediastinic computed tomography that was performed with a modified method as previously described (Choyke et al., 1987); and the quantification of Fig. 1. Evolution of total CD4 cells counts and TRECs. TRECs generated during the rearrangement of T cell receptor genes as one proposed molecular marker for the determination of recent thymic cell emigrants. A PCR-based method for quantifying ␦Rec-J␣ TREC number has been described (Douek et al., 1998). 4. Results Evolution of total CD4 cell counts and TRECs are showed in Fig. 1. Thymic volume was 1.2 cm3 (score 2), which has been related with an attrofic thymus and fat infiltration. Evolution of plasma viral load VIH and CMV are showed in Fig. 2. Plasma viral load CMV was measured in blood samples since year 1993 and it revealed that CMV was detectable in plasma 2 months before starting HAART. It increased until 738,000 copies/mL after initiating first HAART regimen. Despite of second HAART and therapy with ganciclovir, foscarnet and cidofovir were started, CMV was always detectable in plasma. 4.1. Necropsy It was procedure as a standard autopsy, with special looking for thymic remnants. Immunohistochemical thymus studies were performed by streptavidine-biotine technique for CD3, CD20 (Dako-labs), CD4, CD8, CD5 (Vitro labs), and pan-cytokeratins (Menarini lab) antibodies, on paraffin embedded sections. The scarce lymphocytes presents were Fig. 2. HIV and CMV plasma viral load evolution. () Plasma viral load CMV; () plasma viral load HIV. S. Gutiérrez et al. / Journal of Clinical Virology 36 (2006) 13–16 Fig. 3. Cytomegalic inclusion bodies in the medullar epithelial cells of thymus. stained with CD3, CD4, CD8, and CD5, with sparse CD20 positive lymphocytes placed between them. Pan-cytokeratins stained most of the cells with intranuclear cytomegalic inclusions. Macroscopic findings were no relevance. Microscopic study showed generalized infection with cytomegalovirus inclusions, mainly in lungs, with lymphocytic interstitial pneumonitis, and adrenal glands, which showed massive necrotizing adrenalitis. Both serious adrenalitis as the pneumonitis explained the cause of death. Other affected organs were the liver, brain, and heart. Thymus showed diffuse cortical atrophy with scarce lymphocytes, and frequent cytomegalic inclusion cells in the core of the medulla (Fig. 3). Neither necrosis nor plasma cell infiltration were presented. Microscopical changes found were according with changes reported in later stages of the thymic process in AIDS patients (Davis, 1984). Cytomegalic inclusion bodies in the medullar epithelial cells were a relevant finding. 15 On the other hand, it has been reported that the loss of CMV-specific CD4 T cell response cause recurrences of CMV retinitis despite of the increase of CD4 cell counts after HAART (Johnson et al., 2001; Komanduri et al., 2001). To the best of our knowledge, there are no reported cases of death for disseminated CMV disease in HIV-positive patients after HAART. Initially, we thought that the patient developed IRD because the presence of P. carinii pneumonia and CMV colitis, coinciding with the introduction of HAART. Moreover, CD4 cell count at baseline was low but increased after treatment. Subsequently, CMV disease was hard to be explained as a IRD due to the increase of CMV plasma viral load 2 months before initiation of HAART, the sudden clinical evolution and the disseminate infection by viables pathogens found after necropsy. Thus, an alternative hypothesis was needed to formulate. In this way, as revealed by the presence of a later AIDS stage thymus with cytomegalic inclusion bodies, there was a serious thymic dysfunction. This might impair the regeneration of new complete peripheral T cell receptor repertoire that could enhance opportunistic infectious diseases, as P. carinii and CMV infection, despite antiretroviral treatment. Despite thymic impairment, thymic function-related markers as, total CD4 cell counts and TREC levels, increased after HAART. We suggested that, CD4 cell counts could have increased by redistribution of the cells within lymph nodes, while decreased T-cell turnover after HAART could explain the increment in TREC levels (Lempicki et al., 2000). Cytomegalic inclusion bodies found in thymic medullar epithelial cells is a relevant finding since these cells have been reported to be prominent targets of viral replication in different cultures, although it has not been studied in animal models (Mocarski et al., 1993; Numazaki et al., 1989). In conclusion, this case report stands out the difficulty to make an IRD diagnosis. In this way, the development of opportunistic infectious coinciding early after initiating HAART should be considered in the differential IRD diagnosis since they have different management and prognosis. 5. Discussion Acknowledgements Our report describes a serious thymic dysfunction in a naı̈ve HIV-infected patient who developed P. carinii pneumonia and disseminate and fatal cytomegalovirus disease within 3 months after initiation of HAART suggesting, since their coincidence in time, an immune restoration disease. Nowadays, most of the atypical manifestations of infectious diseases after HAART are included as IRD. In this way, CMV IRD has frequently been reported as eye disease, including recurrent CMV retinitis or uveitis (Deayton et al., 2000; Stone et al., 2002). Other less common forms of CMV IRD have been reported, such as, pancreatitis, submaxillitis, pseudotumoral colitis, and isolated fever with positive CMV viraemia (Gilquin et al., 1997). Resolution has been observed in all patients after therapy with ganciclovir and foscarnet. This work was supported by Red de Investigaciones en Sida (RIS) from the Ministerio de Sanidad y Consumo, Spain. 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